Methods and kits for volumetric distribution of pharmaceutical agents via the vascular adventitia and microcirculation

ABSTRACT

Methods and kits for delivering pharmaceutical agents to the adventitia and other regions outside the external elastic lamina (EEL) surrounding a blood vessel utilize a catheter having a needle. The needle is positioned in up to 5 mm beyond the EEL and delivers an amount of pharmaceutical agent sufficient to circumferentially permeate around the blood vessel and, in many cases, extend longitudinally and radially along the blood vessel. Confirmation that a delivery aperture of the needle lies beyond the EEL may be required before delivering the pharmaceutical agent.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of application Ser.No. 10/350,314 (Attorney Docket No. 21621-000110US), filed on Jan. 22,2003, which claimed the benefit of each of the following provisionalapplication 60/350,564, filed Jan. 22, 2002 (Attorney Docket No.21621-000900); 60/356,670, filed Apr. 5, 2002 (Attorney Docket No.21621-001000); 60/370,602, filed Apr. 5, 2002 (Attorney Docket No.21621-000100); and 60/430,993, filed Dec. 3, 2002 (Attorney Docket No.21621-001300). The full disclosures of each of these prior provisionaland non-provisional applications are incorporated herein by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention relates generally to medical methods anddevices. More particularly, the present invention relates to medicalmethods and kits for distributing pharmaceutical agents in theadventitial tissue surrounding a blood vessel.

[0004] Coronary artery disease is the leading cause of death andmorbidity in the United States and other western societies. Inparticular, atherosclerosis in the coronary arteries can causemyocardial infarction, commonly referred to as a heart attack, which canbe immediately fatal or, even if survived, can cause damage to the heartwhich can incapacitate the patient. Other coronary diseases which causedeath and incapacitation include congestive heart failure, vulnerable orunstable plaque, and cardiac arrhythmias. In addition to coronary arterydisease, diseases of the peripheral vasculature can also be fatal orincapacitating. Blood clots and thrombus may occlude peripheral bloodflow, leading to tissue and organ necrosis. Deep vein thrombosis in thelegs can, in the worse cases, requiring amputation. Clots in the carotidartery can embolize and travel to the brain, potentially causingischemic stroke.

[0005] While coronary artery bypass surgery is an effective treatmentfor stenosed arteries resulting from atherosclerosis and other causes,it is a highly invasive procedure which is also expensive and whichrequires substantial hospital and recovery time. Percutaneoustransluminal coronary angioplasty (PTCA), commonly referred to asballoon angioplasty, is less invasive, less traumatic, and significantlyless expensive than bypass surgery. Until recently, however, balloonangioplasty has not been considered to be as effective a treatment asbypass surgery. The effectiveness of balloon angioplasty, however, hasimproved significantly with the introduction of stenting which involvesthe placement of a scaffold structure within the artery which has beentreated by balloon angioplasty. The stent inhibits abrupt reclosure ofthe artery and has some benefit in reducing subsequent restenosisresulting from hyperplasia.

[0006] Despite such improvement, patients who have undergone angioplastyprocedures with subsequent stenting still suffer from a high incidenceof restenosis resulting from hyperplasia. Very recently, however,experimental trials have demonstrated that the implanting of stentswhich have been coated with anti-proliferative drugs can significantlyreduce the occurrence of hyperplasia, promising to make combinedangioplasty and stenting a viable alternative to bypass surgery.

[0007] As an alternative to stent-based luminal drug delivery, thedirect delivery of drug into vascular and other luminal walls has beenproposed. For some time, the use of intravascular catheters havingporous balloons, spaced-apart isolation balloons, expandable sleeves,and the like, have been used for releasing drugs into the inner surfaceof the endothelial wall of blood vessels.

[0008] Congestive heart failure and cardiac arrhythmias, althoughsometimes related to coronary artery disease, are usually treateddifferently than are occlusive diseases. Congestive heart failure ismost often treated pharmaceutically, although no particular drugregimens have proven to be highly effective. Proposed mechanicalapproaches for treating congestive heart failure include constraints forinhibiting further dilation of the heart muscle, and pace makers andmechanical devices for enhancing heart function. Cardiac arrhythmias mayalso be treated with drug therapies, and reasonably effectiveintravascular treatments for ablating aberrant conductive paths on theendocardial surfaces also exist. No one treatment, however, for eitherof these conditions is completely effective in all cases.

[0009] Of particular interest to the present invention, catheterscarrying microneedles capable of delivering therapeutic and other agentsdeep into the adventitial layer surrounding blood vessel lumens havebeen described in U.S. Pat. No. 6,547,303, and co-pending applicationSer. No. 09/961,079, filed on Sep. 20, 2001, both having commoninventorship with but different assignment than the present application,the full disclosures of which are incorporated herein by reference.

[0010] Pharmaceutical therapies for coronary artery and other cardiacand vascular diseases can be problematic in a number of respects. First,it can be difficult to achieve therapeutically effective levels of apharmaceutical agent in the cardiac tissues of interest. This isparticularly true of systemic drug delivery, but also true of variousintravascular drug delivery protocols which have been suggested. Therelease of a pharmaceutical agent directly on to the surface of a bloodvessel wall within the heart or the peripheral vasculature frequentlyresults in much or most of the drug being lost into the luminal bloodflow. Thus, drugs which are difficult to deliver across the blood vesselwall will often not be able to reach therapeutically effectiveconcentrations in the targeted tissue. Second, even when drugs aresuccessfully delivered into the blood vessel wall, they will frequentlylack persistence, i.e., the drug will be rapidly released back into theblood flow and lost from the targeted tissues. Third, it is frequentlydifficult to intravascularly deliver a pharmaceutical agent to remoteand/or distributed diseased regions within a blood vessel. Most priorintravascular drug delivery systems, at best, deliver relatively lowconcentrations of the pharmaceutical agent into regions of the bloodvessel wall which are directly in contact with the delivery catheter.Thus, diseased regions which may be remote from the delivery site(s)and/or which include multiple spaced-apart loci may receive little or notherapeutic benefit from the agent being delivered. In particular, mostif not all prior intravascular drug delivery apparatus have been unableto deliver the drug over large volumetric regions of tissue,particularly in a manner which achieves relatively consistent drugconcentrations. Fourth, delivery of a pharmaceutical agent into theblood vessel wall may be insufficient to treat the underlying cause ofdisease. For example, delivery of anti-proliferative agents into theblood vessel wall may have limited benefit in inhibiting the smoothmuscle cell migration which is believed to be a cause of intimalhyperplasia or cell proliferation characteristic of neoplastic diseases.Fifth, the etiology of the vascular disease may itself inhibit effectivedelivery of a pharmaceutical agent. Thus, systems and protocols whichare designed to deliver drug into blood vessel wall at the site ofdisease may be limited in their effectiveness by the nature of thedisease itself.

[0011] For these reasons, it would be desirable to provide additionaland improved methods and kits for the intravascular delivery ofpharmaceutical agents to treat coronary cerebral, hepatic, peripheral,and other vascular diseases. Such additional and improved methods andkits would preferably also be adaptable to treat non-vascular diseases,including cancers and other neoplastic diseases, diseases associatedwith particular organs or other compartmentalized tissue regions, andother conditions which might benefit from remote localized delivery ofdrugs via the vasculature. In particular, it would be beneficial toprovide methods which enhance the therapeutic concentrations of thepharmaceutical agents in diseased and other targeted tissues, not justthe blood vessel walls. For example, it would be particularly desirableif the methods and systems could provide for an extended volumetricdistribution of the delivered pharmaceutical agent including bothlongitudinal and radial spreading from the injection site(s) in order toprovide therapeutic dosage levels of the agent within the heart, liver,or other organ or compartmentalized tissue region. It would be furtherbeneficial if the methods could efficiently deliver the drugs into thetargeted tissue and limit or avoid the loss of drugs into the luminalblood flow. Similarly, it would beneficial to enhance the therapeuticconcentrations of the pharmaceutical agent delivered to a particulartargeted tissue. It would be still further beneficial if the persistenceof such therapeutic concentrations of the pharmaceutical agent in thetissue were also increased, particularly in targeted tissues away fromthe blood vessel wall, including the adventitial tissue surrounding theblood vessel wall. Additionally, it would be beneficial to increase theuniformity and extent of pharmaceutical agent delivery over remote,extended, and distributed regions of the adventitia and other tissuessurrounding the blood vessels. In some instances, it would be beneficialto provide methods which permit the delivery of pharmaceutical agentsthrough the blood vessel walls at non-diseased sites within the bloodvessel, where the agent would then be able to migrate through theadventitia or other tissues to the diseased site(s). At least some ofthese objectives will be met by the inventions described hereinafter.Still further, it would be desirable if such intravascular delivery ofpharmaceutical agents would be useful for treating diseases andconditions of the tissues and organs in addition to those directlyrelated to the heart or vasculature.

[0012] 2. Description of the Background Art

[0013] U.S. Pat. No. 6,547,803 B2, and published Application2003/0171734A1 both having common inventorship with but differentassignment than the present application, describe microneedle catheterswhich may be used in at least some of the methods described in thepresent application. Drug distribution through the collateralcirculation in the heart is discussed in Daschner et al. (1986) J.Cardiovasc. Surg. 581-584; Laham et al. (1999) Drug Met. Disp.27:821-826; Laham et al. (2003) Cath. Cardio. Interv. 58:375-381; andAltman et al. (2003) Lymph. Res. Biol. 1:47-54.

BRIEF SUMMARY OF THE INVENTION

[0014] Methods and kits according to the present invention are able toachieve enhanced concentrations of many pharmaceutical agents intargeted tissues surrounding a blood vessel, particularly adventitialtissues, more particularly coronary adventitial tissues. The methodsrely on intravascular delivery of the pharmaceutical agent using acatheter having a deployable needle, usually a small needle or amicroneedle. The catheter is advanced intravascularly to a targetinjection site (which may or may not be a diseased region) in a bloodvessel. The needle is advanced through the blood vessel wall so that anaperture on the needle is positioned in a perivascular region (definedbelow) surrounding the injection site, and the pharmaceutical agent isdelivered into the perivascular region through the microneedle.

[0015] In particular, the methods of the present invention are intendedfor a volumetric distribution of a pharmaceutical agent in the tissue ofa living host. By “volumetric distribution,” it is meant that thepharmaceutical agent will be able to distribute both longitudinally andradially with respect to the axis of the blood vessel from which theagent is being injected. Typically, the agent will be able to distributeover a distance of at least 1 cm longitudinally and at least 1 cmradially from the site of injection over a time period no greater than60 minutes. Usually, the volumetric distribution will be significantlygreater than that, and a concentration of the agent measured at alllocations at least 2 cm from the delivery site will be at least 10% ofthe concentration at the delivery site, again preferably after a periodof 60 minutes.

[0016] While the present invention does not depend upon an understandingof the distribution mechanism, for completeness, it is noted that theinventors herein believe that this volumetric distribution results fromdelivery of the pharmaceutical agent into the lymphatic microcirculatorysystem surrounding the blood vessel from which the agent is directed.

[0017] Regardless of the actual mechanism, the methods herein preferablyrely on positioning an aperture of the needle within the target bloodvessel so that the aperture lies beyond an external elastic lamina (EEL)of the blood vessel wall by a distance not exceeding 5 mm, usually notexceeding 3 mm, and preferably not exceeding 0.5 mm. The lower end ofthe range is less critical, and it is necessary only that the aperturebe at least partly beyond the other periphery of the EEL. For lymphaticdistribution, it is preferred to deliver pharmaceutical agents havingdimensions which do not exceed 200 nm, as larger substances are notefficiently distributed by the lymphatic distribution system.

[0018] The methods, systems, and kits of the present invention will findparticular use in the coronary vasculature, including the arterial andvenous vasculature, for treating a variety of conditions, includingpost-angioplasty and post-stenting hyperplasia, cardiac failure,coronary revascularization, and the like. The present invention will,however, also find use outside of the coronary vasculature, includingbut not limited to use in the cerebral vasculature, the hepaticvasculature, the peripheral vasculature, and the vasculature of otherorgans and tissue compartments within a patient. The pharmaceuticalagents may be delivered to treat virtually any condition which isamenable to localized drug delivery, including the delivery ofanti-neoplastic agents to treat tumors and other neoplastic conditions,the delivery of antibiotics and other anti-infective agents to treatinfections and other pathogen-based diseases, and the like.

[0019] This delivery protocol has been found to have a number ofunexpected advantages. First, direct injection into the perivascularregion has been found to immediately provide relatively highconcentrations of the pharmaceutical agent in volume immediatelysurrounding the injected tissue. Second, following injection, it hasbeen found that the injected agents will distribute circumferentially tosubstantially uniformly surround the blood vessel at the injection siteas well as longitudinally to reach positions which are 1 cm, 2 cm, 5 cm,or more away from the injection site. In particular, the injectedpharmaceutical agents have been found to distribute transmurallythroughout the endothelial and intimal layers of the blood vessel, aswell as in the media, or muscular layer, of the blood vessel wall. Inthe coronary arteries, in addition to circumferential and longitudinalmigration, the pharmaceutical agent can migrate through the myocardiumto reach the adventitia and wall structures surrounding blood vesselsother than that through which the agent has been injected. Pathways forthe distribution of the pharmaceutical agent are presently believed toexist through the pericardial space and the sub-epicardial space and mayalso exist in the vasa vasorum and other capillary channels through themuscle and connective tissues. Third, the delivered and distributedpharmaceutical agent(s) will persist for hours or days and will releaseback into the blood vessel wall over time. Thus, a prolonged therapeuticeffect based on the pharmaceutical agent may be achieved in both theadventitia and the blood vessel wall. Fourth, after the distribution hasoccurred, the concentration of the pharmaceutical agent throughout itsdistribution region will be highly uniform. While the concentration ofthe pharmaceutical agent at the injection site will always remain thehighest, concentrations at other locations in the peripheral adventitiaaround the injection site will usually reach at least about 10% of theconcentration at the injection site, often being at least about 25%, andsometimes being at least about 50%. Similarly, concentrations in theadventitia at locations longitudinally separated from the injection siteby about 5 cm will usually reach at least 5% of the concentration at theinjection site, often being at least 10%, and sometimes being at least25%. Finally, the methods of the present invention will allow for theinjection of pharmaceutical agents through non-diseased regions of thecoronary and peripheral vasculature to treat adjacent or remote diseasedregions of the vasculature. The latter is of particular advantage sincethe diseased regions may be refractory to effective microneedle or otherintravascular delivery protocols. Thus, pharmaceutical agent(s) can bedelivered into the adventitia surrounding the diseased regions throughremote injection sites.

[0020] The benefits of the present invention are achieved by deliveringthe pharmaceutical agents into a perivascular region surrounding acoronary artery or other blood vessel. The perivascular region isdefined as the region beyond external elastic lamina of an artery orbeyond the tunica media of a vein. Usually, injection will be madedirectly into the vasa vasorum region of the adventitia, and it has beenfound that the pharmaceutical agent disperses through the adventitiacircumferentially, longitudinally, and transmurally from injection site.Such distribution can provide for delivery of therapeutically effectiveconcentrations of many drugs which would be difficult to administer inother ways.

[0021] The adventitia is a layer of fatty tissue surrounding thearteries of the human and other vertebrate cardiovascular systems. Theexternal elastic lamina (EEL) separates the fatty adventitial tissuefrom muscular tissue that forms the arterial wall. Microneedles of thepresent invention pass through the muscular tissue of the blood vesseland the EEL in order to reach the perivascular space into which the drugis injected. The drugs will typically either be in fluid formthemselves, or will be suspended in aqueous or fluid carriers in orderto permit dispersion of the pharmaceutical agents through theadventitia.

[0022] The adventitial tissue has a high concentration of lipids whichwill preferentially solubilize lipophilic pharmaceutical agents andhydrophilic or other pharmaceutical agents which are incorporated intolipophilic carriers, adjuvants, or the like. Both lipophilic andnon-lipophilic pharmaceutical agents will have the ability to diffusewithin and through the adventitia, with the rate and extent of suchdiffusion being controlled, at least in part, by the degree and natureof the lipophilic moieties present in the pharmaceutical agents. Thus,when pharmaceutical agents are injected, either by themselves or in anaqueous carrier, the agents may tend to be preferentially absorbed bythe lipids in the adventitia. Pharmaceutical agents do not, however,remain localized at the site of injection, but instead will migrate andspread through the adventitia to locations remote from the injectionsite. The affinity between the pharmaceutical agents and the lipids inthe adventitia, however, will provide for a controlled and sustainedrelease of the lipophilic and other pharmaceutical agents over time.Thus, delivery of pharmaceutical agents into the adventitia creates abiological controlled release system for the agents. In particular, thepharmaceutical agents will slowly be released back from the adventitiainto the muscle and other layers of the blood vessel wall to provide forprolonged pharmacological treatment of those areas. Such prolongedtreatments can be particularly useful for inhibiting vascularhyperplasia and other conditions which are thought to initiate withinthe smooth muscle cells and other components of the blood vessel wall.

[0023] Pharmaceutical agents formulated to provide for sustained orcontrolled release of the pharmacologically active substances may beintroduced directly into the adventitia by injection using themicroneedle of the present invention. Numerous particular controlledrelease formulations are known in the art. Exemplary formulationsinclude those which provide for diffusion through pores of amicrocarrier or other particle, erosion of particles or barrier films,and combinations thereof. In addition, microparticles or nanoparticlesof pure (neat) pharmaceutical substances may be provided. Cross-linkedforms of such substances may also be utilized, and combinations thereofwith erodable polymers may be employed. Other conventional formulations,such as liposomes, solubilizers (e.g. cyclodextrins), and the like, maybe provided to control release of the active substance in thepharmaceutical agent.

[0024] In a first aspect of the present invention, a method fordistributing a pharmaceutical agent in the adventitial tissue of aliving vertebrate host's heart, such as a human heart, comprisespositioning a microneedle through the wall of a coronary blood vesseland delivering an amount of the pharmaceutical agent therethrough. Theaperture of the microneedle is located in a perivascular spacesurrounding the blood vessel, and the pharmaceutical agent distributessubstantially completely circumferentially through adventitial tissuesurrounding the blood vessel at the site of the microneedle. Usually,the agent will further distribute longitudinally along the blood vesselover a distance of at least 1 cm, often a distance of a least 5 cm, andsometimes a distance of at least 10 cm, within a time period no greaterthan 60 minutes, often within 5 minutes of less. While the concentrationof the pharmaceutical agent in the adventitia will decrease in thelongitudinal direction somewhat, usually, the concentration measured ata distance of 5 cm from the injection site will be at least 5% of theconcentration measured at the same time at the injection site, oftenbeing at least 10%, frequently being as much as 25%, and sometimes beingas much as 50%.

[0025] The aperture of the microneedle will be positioned so that itlies beyond the external elastic lamina (EEL) of the blood vessel walland into the perivascular region surrounding the wall. Usually, theaperture will be positioned at a distance from the inner wall of theblood vessel which is equal to at least 10% of the mean luminal diameterof the blood vessel at the injection site. Preferably, the distance willbe in the range from 10% to 75% of the mean luminal diameter. Theamounts of the pharmaceutical agent delivered into the perivascularregion may vary considerably, but will typically be in the range from 10μl to 5000 μl, typically being from 100 μl to 1000 μl, and often beingfrom 250 μl to 500 μl. Such methods for distributing pharmaceuticalagents will be most often used in coronary arteries, typically for thetreatment of hyperplasia or vulnerable plaque. The methods may furtherfind use, however, in patients suffering from other vascular diseases,such as those in the peripheral vasculature, and in patients sufferingfrom coronary conditions, including congestive heart failure, cardiacarrhythmias, and the like. In the latter cases, the methods of thepresent invention are particularly useful in delivering pharmaceuticalagents widely and uniformly through the myocardium by using one or arelatively low number of injections in the coronary vasculature.

[0026] In a second aspect of the present invention, methods for depotinga lipophilic or other pharmaceutical agent in the adventitial tissue ofa living vertebrate host, typically a human heart or other tissue,comprise positioning a microneedle through the wall of a coronary bloodvessel and delivering an amount of the pharmaceutical agent into theperivascular space surrounding the blood vessel. The agent is deliveredthrough an aperture in the microneedle directly into the perivascularspace so that it distributes within the adventitial tissue surroundingthe blood vessel. As described generally above, the interaction betweenthe pharmaceutical agent and the lipid-containing adventitia provide fora depot or reservoir of the drug which is subsequently released into theblood vessel wall and other tissues in a controlled fashion over time.While the depoting pharmaceutical agent in the coronary adventitialtissue may find the greatest use, the depoting and release of drugs fromother adventitial tissues located surrounding the peripheral vasculaturewill also find use in the treatment of peripheral vascular disease, aswell as diseases of other organs and tissues.

[0027] Exemplary pharmaceutical agents for treating restenosis andhyperplasia include antiproliferative agents, immunosuppressive agents,anti-inflammatory agents, macrolide antibiotics, statins, anti-senseagents, metalloproteinase inhibitors, and cell cycle inhibitors andmodulators. Agents for the treatment of arrhythmia include amiodarone,ibutilide, and mexiletine. Agents for the treatment of congestive heartfailure include beta blockers, nitric oxide releasers, angiotensinconverting enzyme inhibitors, and calcium channel antagonists. Agentsfor treatment of vulnerable (unstable) plaque include macrolideantibiotics, anti-inflammatory agents, statins, and thioglitazones.Agents for the treatment of vasospasm include cerapamil, and lapararin.A more complete listing of pharmaceutical agents suitable for treatingcoronary, vascular, and other diseased tissues and organs in accordancewith the principles of the present invention is set forth in Table Ibelow.

[0028] In a third aspect of the present invention, a method fordelivering a pharmaceutical agent to a diseased treatment region in acoronary blood vessel comprises positioning a microneedle through thewall of a coronary artery at a delivery site spaced-apart from thediseased treatment region. The delivery site may be located within thesame blood vessel as the diseased treatment region at a location whichis longitudinally spaced-apart from said region, or may be located in adifferent blood vessel, including a different artery, or more usually,in a cognate coronary vein. In all cases, an amount of thepharmaceutical agent is delivered through an aperture in the microneedleinto a perivascular space surrounding the delivery site so that theagent distributes into adventitial tissue surrounding the diseasedtreatment region to provide for the desired therapy. In some instances,the diseased treatment region may have been previously stented where thedelivery site is spaced away from the stent, either longitudinally awayfrom the stent in the same coronary artery or remote from the stent inanother coronary artery or vein.

[0029] In still further aspects of the present invention, kits fordelivering pharmaceutical agents to a patient suffering from or at riskof coronary artery or other vascular or non-vascular disease comprise acatheter and instructions for use of the catheter. The catheter has amicroneedle which can be advanced from a blood vessel lumen through awall of the blood vessel to position an aperture of the microneedle at aperivascular space surrounding the blood vessel. The instructions foruse set forth any of the three exemplary treatment protocols describedabove.

[0030] The present invention still further comprises the use of acatheter having a microneedle in the manufacture of an apparatus fordelivering pharmaceutical agents to a patient suffering from coronaryartery disease. The pharmaceutical agent is delivered from a bloodvessel lumen into a perivascular space surrounding the blood vessel sothat the agent distributes circumferentially through the adventitialtissue surrounding the blood vessel. Usually, the agent will alsodistribute longitudinally along the blood vessel over a distance of atleast 5 cm within a time of no greater than 5 minutes, usually within 1minute or less. In some cases, the agent may further distribute intoregions of the adventitia surrounding other blood vessels.

[0031] In another aspect of the present invention, methods and apparatusare provided for confirming that the aperture of the pharmaceuticalagent injection needle is present beyond the external elastic lamina(EEL) before delivering pharmaceutical agent. As discussed above, itwill often be desirable to place the delivery aperture of thepharmaceutical agent delivery needle just beyond the outside peripheryor perimeter of the EEL prior to injection of the desired pharmaceuticalagent. The difficulty with such positioning is that the thickness of theEEL can vary significantly, typically being from 0.1 mm to 5 mm thick,usually being less than 3 mm thick. The effective deployed needle lengthmay not always be sufficient to assure that the delivery aperture is inthe preferred 0 mm to 5 mm cylindrical envelope region outside of theEEL. Moreover, variations in thickness of plaque and other obstructivematerial which may be present on the interior of the blood vessel canalso affect the ability of the needle to penetrate the vascular wall andposition the delivery aperture at the requisite distance beyond theperiphery of the EEL. Thus, in order to assure that the drug will enterthis preferred cylindrical envelope surrounding the blood vessel, it isuseful to confirm the position of the delivery aperture prior todelivery of the pharmaceutical agent.

[0032] Confirmation of the position of the pharmaceutical agent deliveryaperture can be achieved in a variety of ways. Most simply, a bolus ofradio opaque contrast agent or other visible media can be injectedthrough the needle after initial positioning of the needle is achieved.By then observing the distribution of the media, usuallyfluoroscopically, the position of the aperture can be assessed. If theneedle still lies within the EEL, the bolus will remain contained withinthe wall and will appear to have well defined edges and will usuallytaper longitudinally as the wall is dissected. If the aperture isproperly positioned outside of the EEL, in contrast, the media willdiffuse longitudinally along the vessel in the desired pattern. Finally,if the needle has extended beyond the preferred adventitial space andinto muscle, the media will usually follow a non-homogenous diffusionpattern between the muscle fibers. Only when the desired patterncharacteristic of adventitial delivery is confirmed will thepharmaceutical agent then be delivered.

[0033] In other cases, various sensors can be attached or otherwisecoupled to the delivery needle, usually near the delivery aperture, inorder to detect the position of the needle. Useful sensors includetemperature sensors, pH sensors, electrical impedance sensors, and thelike. It is also possible to measure back pressure on an injected fluid,either saline or other non-active agent or the pharmaceutical agentitself, in order to determine the needle position. Injection into theblood vessel wall will typically result in a greater back pressure thaninjection into the adventitial space. It will also be possible tomonitor the insertion force of the needle, e.g., by providing adeflection gauge on a portion of the needle, or otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034]FIG. 1 is a schematic illustration of a coronary artery togetherwith surrounding tissue illustrating the relationship between theperivascular space, the adventitia, and the blood vessel wallcomponents.

[0035]FIG. 1A is a schematic, perspective view of a microfabricatedsurgical device for interventional procedures in accordance with themethods and kits of the present invention in an unactuated condition.

[0036]FIG. 1B is a schematic view along line 1B-1B of FIG. 1A.

[0037]FIG. 1C is a schematic view along line 1C-1C of FIG. 1A.

[0038]FIG. 1D is a schematic illustration of a microneedle having anaperture positioned at a preferred distance beyond the external elasticlamina (EEL) in accordance with the principles of the present invention.

[0039]FIG. 1E illustrates the volumetric drug distribution achieved bythe microneedle positioning of FIG. 1D.

[0040]FIG. 2A is a schematic, perspective view of the microfabricatedsurgical device of FIG. 1A in an actuated condition.

[0041]FIG. 2B is a schematic view along line 2B-2B of FIG. 2A.

[0042]FIG. 3 is a schematic, perspective view of the microfabricatedsurgical device of the present invention inserted into a patient'svasculature.

[0043] FIGS. 3A-3C illustrate the injection of a radio contrast media tohelp determine whether the pharmaceutical agent delivery aperture of aninjection needle is properly placed within the preferred adventitialspace surrounding a blood vessel.

[0044]FIG. 3D illustrates the optional placement of sensors on a druginjection needle, which sensors can detect whether the needle has beenadvanced into the preferred adventitial space surrounding a bloodvessel.

[0045]FIG. 4 is a schematic, perspective view of another embodiment ofthe device of the present invention.

[0046]FIG. 5 is a schematic, perspective view of still anotherembodiment of the present invention, as inserted into a patient'svasculature.

[0047]FIGS. 6A and 6B illustrate the initial stage of the injection of apharmaceutical agent into a perivascular space using the catheter ofFIG. 3. FIG. 6A is a view taken across the blood vessel and FIG. 6B is aview taken along the longitudinal length of the blood vessel.

[0048]FIGS. 7A and 7B are similar to FIGS. 6A and 6B showing the extentof pharmaceutical agent distribution at a later time after injection.

[0049]FIGS. 8A and 8B are again similar to FIGS. 6A and 6B showing theextent of pharmaceutical agent distribution at a still later timefollowing injection.

[0050]FIGS. 9 and 10 illustrate data described in the Experimentalsection herein.

DETAILED DESCRIPTION OF THE INVENTION

[0051] The present invention will preferably utilize microfabricatedcatheters for intravascular injection. The following descriptionprovides two representative embodiments of catheters having microneedlessuitable for the delivery of a pharmaceutical agent into a perivascularspace or adventitial tissue. A more complete description of thecatheters and methods for their fabrication is provided in U.S. Pat. No.6,547,803 B2 the full disclosure of which has been incorporated hereinby reference.

[0052] The perivascular space is the potential space over the outersurface of a “vascular wall” of either an artery or vein. Referring toFIG. 1, a typical arterial wall is shown in cross-section where theendothelium E is the layer of the wall which is exposed to the bloodvessel lumen L. Underlying the endothelium is the basement membrane BMwhich in turn is surrounded by the intima I. The intima, in turn, issurrounded by the internal elastic lamina IEL over which is located themedia M. In turn, the media is covered by the external elastic lamina(EEL) which acts as the outer barrier separating the arterial wall,shown collectively as W, from the adventitial layer A. Usually, theperivascular space will be considered anything lying beyond the externalelastic lamina EEL, including regions within the adventitia and beyond.

[0053] The microneedle is inserted, preferably in a substantially normaldirection, into the wall of a vessel (artery or vein) to eliminate asmuch trauma to the patient as possible. Until the microneedle is at thesite of an injection, it is positioned out of the way so that it doesnot scrape against arterial or venous walls with its tip. Specifically,the microneedle remains enclosed in the walls of an actuator or sheathattached to a catheter so that it will not injure the patient duringintervention or the physician during handling. When the injection siteis reached, movement of the actuator along the vessel terminated, andthe actuator is operated to cause the microneedle to be thrustoutwardly, substantially perpendicular to the central axis of a vessel,for instance, in which the catheter has been inserted.

[0054] As shown in FIGS. 1A-2B, a microfabricated intravascular catheter10 includes an actuator 12 having an actuator body 12 a and centrallongitudinal axis 12 b. The actuator body more or less forms a C-shapedoutline having an opening or slit 12 d extending substantially along itslength. A microneedle 14 is located within the actuator body, asdiscussed in more detail below, when the actuator is in its unactuatedcondition (furled state) (FIG. 1B). The microneedle is moved outside theactuator body when the actuator is operated to be in its actuatedcondition (unfurled state) (FIG. 2B).

[0055] The actuator may be capped at its proximal end 12 e and distalend 12 f by a lead end 16 and a tip end 18, respectively, of atherapeutic catheter 20. The catheter tip end serves as a means oflocating the actuator inside a blood vessel by use of a radio opaquecoatings or markers. The catheter tip also forms a seal at the distalend 12 f of the actuator. The lead end of the catheter provides thenecessary interconnects (fluidic, mechanical, electrical or optical) atthe proximal end 12 e of the actuator.

[0056] Retaining rings 22 a and 22 b are located at the distal andproximal ends, respectively, of the actuator. The catheter tip is joinedto the retaining ring 22 a, while the catheter lead is joined toretaining ring 22 b. The retaining rings are made of a thin, on theorder of 10 to 100 microns (μm), substantially rigid material, such asparylene (types C, D or N), or a metal, for example, aluminum, stainlesssteel, gold, titanium or tungsten. The retaining rings form a rigidsubstantially “C”-shaped structure at each end of the actuator. Thecatheter may be joined to the retaining rings by, for example, abutt-weld, an ultra sonic weld, integral polymer encapsulation or anadhesive such as an epoxy.

[0057] The actuator body further comprises a central, expandable section24 located between retaining rings 22 a and 22 b. The expandable section24 includes an interior open area 26 for rapid expansion when anactivating fluid is supplied to that area. The central section 24 ismade of a thin, semi-rigid or rigid, expandable material, such as apolymer, for instance, parylene (types C, D or N), silicone,polyurethane or polyimide. The central section 24, upon actuation, isexpandable somewhat like a balloon-device.

[0058] The central section is capable of withstanding pressures of up toabout 100 atmospheres upon application of the activating fluid to theopen area 26. The material from which the central section is made of isrigid or semi-rigid in that the central section returns substantially toits original configuration and orientation (the unactuated condition)when the activating fluid is removed from the open area 26. Thus, inthis sense, the central section is very much unlike a balloon which hasno inherently stable structure.

[0059] The open area 26 of the actuator is connected to a deliveryconduit, tube or fluid pathway 28 that extends from the catheter's leadend to the actuator's proximal end. The activating fluid is supplied tothe open area via the delivery tube. The delivery tube may beconstructed of Teflon© or other inert plastics. The activating fluid maybe a saline solution or a radio-opaque dye.

[0060] The microneedle 14 may be located approximately in the middle ofthe central section 24. However, as discussed below, this is notnecessary, especially when multiple microneedles are used. Themicroneedle is affixed to an exterior surface 24 a of the centralsection. The microneedle is affixed to the surface 24 a by an adhesive,such as cyanoacrylate. The mesh-like structure (if included) may be-madeof, for instance, steel or nylon.

[0061] The microneedle includes a sharp tip 14 a and a shaft 14 b. Themicroneedle tip can provide an insertion edge or point. The shaft 14 bcan be hollow and the tip can have an outlet port 14 c, permitting theinjection of a pharmaceutical or drug into a patient. The microneedle,however, does not need to be hollow, as it may be configured like aneural probe to accomplish other tasks.

[0062] As shown, the microneedle extends approximately perpendicularlyfrom surface 24 a. Thus, as described, the microneedle will movesubstantially perpendicularly to an axis of a vessel or artery intowhich has been inserted, to allow direct puncture or breach of vascularwalls.

[0063] The microneedle further includes a pharmaceutical or drug supplyconduit, tube or fluid pathway 14 d which places the microneedle influid communication with the appropriate fluid interconnect at thecatheter lead end. This supply tube may be formed integrally with theshaft 14 b, or it may be formed as a separate piece that is later joinedto the shaft by, for example, an adhesive such as an epoxy.

[0064] The needle 14 may be a 30-gauge, or smaller, steel needle.Alternatively, the microneedle may be microfabricated from polymers,other metals, metal alloys or semiconductor materials. The needle, forexample, may be made of parylene, silicon or glass. Microneedles andmethods of fabrication are described in U.S. patent publication2002/0188310, entitled “Microfabricated Surgical Device”, having commoninventorship with but different assignment than the subject application,the entire disclosure of which is incorporated herein by reference.

[0065] The catheter 20, in use, is inserted through an artery or veinand moved within a patient's vasculature, for instance, an artery 32,until a specific, targeted region 34 is reaches (see FIG. 3). As is wellknown in catheter-based interventional procedures, the catheter 20 mayfollow a guide wire 36 that has previously been inserted into thepatient. Optionally, the catheter 20 may also follow the path of apreviously-inserted guide catheter (not shown) that encompasses theguide wire.

[0066] During maneuvering of the catheter 20, well-known methods offluoroscopy or magnetic resonance imaging (MRI) can be used to image thecatheter and assist in positioning the actuator 12 and the microneedle14 at the target region. As the catheter is guided inside the patient'sbody, the microneedle remains unfurled or held inside the actuator bodyso that no trauma is caused to the vascular walls.

[0067] After being positioned at the target region 34, movement of thecatheter is terminated and the activating fluid is supplied to the openarea 26 of the actuator, causing the expandable section 24 to rapidlyunfurl, moving the microneedle 14 in a substantially perpendiculardirection, relative to the longitudinal central axis 12 b of theactuator body 12 a, to puncture a vascular wall 32 a. It may take onlybetween approximately 100 milliseconds and two seconds for themicroneedle to move from its furled state to its unfurled state.

[0068] The ends of the actuator at the retaining rings 22 a and 22 bremain rigidly fixed to the catheter 20. Thus, they do not deform duringactuation. Since the actuator begins as a furled structure, itsso-called pregnant shape exists as an unstable buckling mode. Thisinstability, upon actuation, produces a large-scale motion of themicroneedle approximately perpendicular to the central axis of theactuator body, causing a rapid puncture of the vascular wall without alarge momentum transfer. As a result, a microscale opening is producedwith very minimal damage to the surrounding tissue. Also, since themomentum transfer is relatively small, only a negligible bias force isrequired to hold the catheter and actuator in place during actuation andpuncture.

[0069] The microneedle, in fact, travels so quickly and with such forcethat it can enter perivascular tissue 32 b as well as vascular tissue.Additionally, since the actuator is “parked” or stopped prior toactuation, more precise placement and control over penetration of thevascular wall are obtained.

[0070] After actuation of the microneedle and delivery of thepharmaceutical to the target region via the microneedle, the activatingfluid is exhausted from the open area 26 of the actuator, causing theexpandable section 24 to return to its original, furled state. This alsocauses the microneedle to be withdrawn from the vascular wall. Themicroneedle, being withdrawn, is once again sheathed by the actuator.

[0071] By way of example, the microneedle may have an overall length ofbetween about 200 and 3,000 microns (μm). The interior cross-sectionaldimension of the shaft 14 b and supply tube 14 d may be on the order of20 to 250 μm, while the tube's and shaft's exterior cross-sectionaldimension may be between about 100 and 500 μm. The overall length of theactuator body may be between about 5 and 50 millimeters (mm), while theexterior and interior cross-sectional dimensions of the actuator bodycan be between about 0.4 and 4 mm, and 0.5 and 5 mm, respectively. Thegap or slit through which the central section of the actuator unfurlsmay have a length of about 4-40 mm, and a cross-sectional dimension ofabout 50-500 μm. The diameter of the delivery tube for the activatingfluid may be about 100 μm to 1000 μm. The catheter size may be between1.5 and 15 French (Fr).

[0072] Methods of the present invention may also utilize amultiple-buckling actuator with a single supply tube for the activatingfluid. The multiple-buckling actuator includes multiple needles that canbe inserted into or through a vessel wall for providing injection atdifferent locations or times. For instance, as shown in FIG. 4, theactuator 120 includes microneedles 140 and 142 located at differentpoints along a length or longitudinal dimension of the central,expandable section 240. The operating pressure of the activating fluidis selected so 110 that the microneedles move at the same time.Alternatively, the pressure of the activating fluid may be selected sothat the microneedle 140 moves before the microneedle 142.

[0073] Specifically, the microneedle 140 is located at a portion of theexpandable section 240 (lower activation pressure) that, for the sameactivating fluid pressure, will buckle outwardly before that portion ofthe expandable section (higher activation pressure) where themicroneedle 142 is located. Thus, for example, if the operating pressureof the activating fluid within the open area of the expandable section240 is two pounds per square inch (psi), the microneedle 140 will movebefore the microneedle 142. It is only when the operating pressure isincreased to four psi, for instance, that the microneedle 142 will move.Thus, this mode of operation provides staged buckling with themicroneedle 140 moving at time t₁, and pressure p₁, and the microneedle142 moving at time t₂ and p₂, with t₁, and p₁, being less than t₂ andp₂, respectively.

[0074] This sort of staged buckling can also be provided with differentpneumatic or hydraulic connections at different parts of the centralsection 240 in which each part includes an individual microneedle.

[0075] Also, as shown in FIG. 5, an actuator 220 could be constructedsuch that its needles 222 and 224A move in different directions. Asshown, upon actuation, the needles move at angle of approximately 90° toeach other to puncture different parts of a vessel wall. A needle 224B(as shown in phantom) could alternatively be arranged to move at angleof about 180° to the needle 224A.

[0076] Referring now to FIGS. 6A/6B through FIGS. 8A/8B, use of thecatheter 10 of FIGS. 1-3 for delivering a pharmaceutical agent accordingto the methods of the present invention will be described. The catheter10 may be positioned so that the actuator 12 is positioned at a targetsite for injection within a blood vessel, as shown in FIGS. 6A/6B. Theactuator penetrates the needle 14 through the wall W so that it extendspast the external elastic lamina (EEL) into the perivascular spacesurrounding the EEL. Once in the perivascular space, the pharmaceuticalagent may be injected, typically in a volume from 10 μl to 5000 μl,preferably from 100 μl to 1000 μl, and more preferably 250 μl to 500 μl,so that a plume P appears. Initially, the plume occupies a spaceimmediately surrounding an aperture in the needle 14 and extendingneither circumferentially nor longitudinally relative toward theexternal wall W of the blood vessel. After a short time, typically inthe range from 1 to 10 minutes, the plume extends circumferentiallyaround the external wall W of the blood vessel and over a short distancelongitudinally, as shown in FIGS. 7A and 7B, respectively. After a stillfurther time, typically in the range from 5 minutes to 24 hours, theplume will extend substantially completely circumferentially, asillustrated in FIG. 8A, and will begin to extend longitudinally overextended lengths, typically being at least about 2 cm, more usuallybeing about 5 cm, and often being 10 cm or longer, as illustrated inFIG. 8B.

[0077] Referring now to FIGS. 1D and 1E, a preferred protocol forpositioning the aperture 300 of a microneedle 314 for volumetricdelivery of a pharmaceutical agent in accordance with the principles ofthe present invention will be described. The aperture 300 is positionedfrom the lumen L of a blood vessel using any of the microneedle cathetersystems described above. In particular, aperture 300 of the microneedle314 is positioned beyond the external elastic lamina EEL by a distanceof 5 mm or less, preferably 3 mm or less, and usually 0.5 mm or less, asdescribed previously. To position the aperture within the requisitedistance beyond the EEL, the needle must pass through the other layersof the blood vessel, as described above, in connection with FIG. 1A.Usually, these underlying layers will have a total thickness in therange from 0.1 mm to 5 mm, requiring that the needle extend from theblood vessel by a distance which is greater than the thickness of thewall. Once in position, the aperture 300 releases the pharmaceuticalagent which then begins to form a plume P, as illustrated in FIG. 1D. Bypositioning beyond the blood vessel wall, but less than the 5 mm limit,it has been found that extensive volumetric distribution of thepharmaceutical agent can be achieved, as shown in FIG. 1E.

[0078] Because of variability in blood vessel wall thickness andobstructions which may limit the penetration depth of the needle beingdeployed, it will often be desirable to confirm that the pharmaceuticalagent delivery aperture of the injection needle is present in the 5 mmannular envelope surrounding the delivery blood vessel prior toinjection. Such confirmation can be achieved in a variety of ways.

[0079] Referring to FIGS. 3A through 3C, the needle 14 of FIG. 3 can bepositioned through the vascular wall so that it lies beyond the externalelastic lamina (EEL), as shown in broken line in FIG. 3A. So long as theaperture 14 a lies beyond the periphery of the EEL, and preferably a 5mm annulus surrounding the vessel, successful delivery of thepharmaceutical agent can usually be achieved. To confirm that theaperture 14 a lies within this target annual region, a bolus of contrastmedia can be injected prior to delivery of the pharmaceutical agent. Ifthe aperture 14 a has not penetrated through the EEL, as shown in FIG.3B, then the bolus of contrast media will remain constrained within thewall of the vessel forming a well defined, generally tapered or ovoidmass B, as shown in FIG. 3B. In contrast, if the aperture 14 a ispositioned beyond the EEL, and within the desired annular region, thebolus B will spread longitudinally along the blood vessel wall in a veryshort period of time, indicating that the drug may be affectivelydelivered, as shown in FIG. 3C.

[0080] Other methods for confirming that the aperture 14 a is properlypositioned rely on presence of a sensor(s) 15 and/or located on theneedle 14 usually near the aperture. Sensor 15 may be a solid statepressure sensor. If the pressure builds up during injection (either ofan inactive agent or the pharmaceutical agent, it is likely that theaperture 14 a still lies within the blood vessel wall. If the pressureis lower, the physician can assume that the needle has reached theadventitia. Sensor 15 may also be a temperature, such as a smallthermistor or thermocouple, located at the tip of the needle adjacentover then the aperture 14 a. The temperature within the blood vesselwall will be different than that outside of the EEL, making positionfunction of temperature. The sensor may be a pH detector, where thetissue within the blood vessel wall and beyond the EEL have detectabledifferences in pH. Similarly, electrical impedance measurementscharacteristic of the tissues may be made with an impedance sensor 15. Adeflection sensor 17, such as a flexible straining gauge, may beprovided on a portion of the needle 14 which will deflect in response toinsertion force. Insertion force through the blood vessel wall will behigher than that necessary to penetrate the tissue beyond the EEL. Thus,entry into the tissue beyond the EEL can be confirmed when the insertionforce measured by the sensor 17 falls.

[0081] As just described, of course, the extent of migration of thepharmaceutical agent is not limited to the immediate region of the bloodvessel through which the agent is been injected into the perivascularspace. Instead, depending on the amounts injected and other conditions,the pharmaceutical agent may extend further into and through themyocardium other connective tissues so that it surrounds theextravascular spaces around other blood vessels, including both arteriesand veins. As also described above, such broad myocardial, epicardial,or pericardial delivery can be particularly useful for treatingnon-localized cardiac conditions, such as conditions associated withcongestive heart failure conditions associated with vulnerable orunstable plaque and conditions associated with cardiac arrhythmias.Delivery and diffusion of a pharmaceutical agent into a peripheralextravascular space can be particularly useful for treating diffusevascular diseases.

[0082] The methods and kits described above may be used to deliver awide variety of pharmaceutical agents intended for both local andnon-local treatment of the heart and vasculature. Exemplarypharmaceutical agents include antineoplastic agents, antiproliferativeagents, cytostatic agents, immunosuppressive agents, anti-inflammatoryagents, macrolide antibiotics, antibiotics, antifungals, antivirals,antibodies, lipid lowering treatments, calcium channel blockers, ACEinhibitors, gene therapy agents, anti-sense drugs, double stranded shortinterfering RNA molecules, metalloproteinase inhibitors, growth factorinhibitors, cell cycle inhibitors, angiogenesis drugs, anti-angiogenesisdrugs, and/or iadiopaque contrast media for visualization of theinjection under guided X-ray fluoroscopy. Each of these therapeuticagents has shown promise in the treatment of cardiovascular disease,restenosis, congestive heart failure, and/or vulnerable plaque lesions.Particular agents are set forth in TABLE I 1. Antiproliferative agents,immunosuppressive agents, cytostatic, and anti-inflammatory agents,including but not limited to sulindac, tranilast, ABT-578, AVI-4126,sirolimus, tacrolimus, everolimus, cortisone, dexamethosone,cyclosporine, cytochalisin D, valsartin, methyl prednisolone,thioglitazones, acetyl salicylic acid, sarpognelate, and nitric oxidereleasing agents, which interfere with the pathological proliverativeresponse after coronary antioplasty to prevent intimal hyperplasia,smooth muscle cell activation and migration, and neointimal thickening.2. Antineoplastic agents, including but not limited to paclitaxel,actinomycin D, and latrunculin A, which interfere with the pathologicalproliferative response after coronary angioplasty to prevent intimalhyperplasia, smooth muscle activation and migration and neointimalthickening. 3. Macrolide antibiotics, including but not limited tosirolimus, tacrolimus, everolimus, azinthromycin, clarithromycin, anderythromycin, which inhibit or kill microorganiss that may contribute tothe inflammatory process that triggers or exacerbates restenosis andvulnerable plaque. In addition many macrolide antibiotics, including butnot limited to sirolimus and tacrolimus, have immunosuppressive effectsthat can prevent intimal hyperplasia, neointimal proliferation, andplaque rupture. Other antibiotics, including but not limited tosirolumus, tacrolimus, everolimus, azithromycin, clarithromycin,doxycycline, and erothromycin, inhibit or kill microorganisms that maycontribute to the inflammatory process that triggers or exacerbatesrestenosis and vulnerable plaque. 4. Antivirals, including but notlimited to acyclovir, ganciclovir, fancyclovir and valacyclovir, inhibitor kill viruses that may contribute to the inflammatory process thattriggers or exacerbates restenosis and vulnerable plaque. 5. Antibodieswhich inhibit or kill microorganisms that may contribute to theinflammatory process that triggers or exacerbates restenosis andvulnerable plaque or to inhibit specific growth factors or cellregulators. 6. Lipid-lowering treatments, including but not limited tostatins, such as trichostatin A, which modify plaques, reducinginflammation and stabilizing vulnerable plaques. 7. Gene therapy agentswhich achieve overexpression of genes that may ameliorate the process ofvascular occlusive disease or the blockade of the expression of thegenes that are critical to the pathogenesis of vascular occlusivedisease. 8. Anti-sense agents, including but not limited to AVI-4126,achieve blockade of genes and mRNA, including but not limited to c-myc,c-myb, PCNA, cdc2, cdk2, or cdk9s, through the use of short chains ofnucleic acids known as antisense oligodeoxynucleotides. 9.Metalloproteinase inhibitors, including but not limited to batimastat,inhibit constrictive vessel remodeling. 10. Cell cycle inhibitors andmodulators and growth factor inhibitors and modulators, including butnot limited to cytokine receptor inhibitors, such as interleukin 10 orpropagermanium, and modulators of VEGF, IGF, and tubulin, inhibit ormodulate entry of vascular smooth muscle cells into the cell cycle, cellmigration, expression chemoattractants and adhesion molecules,extracellular matrix formation, and other factors that triggerneointimal hyperplasia. 11. Angiogenesis genes or agents which increasemicrovasculature of the pericardium, vaso vasorum, and adventitia toincrease blood flow. 12. Anti-angiogenesis genes or agents inhibitfactors that are associated with microvascularization of atheroscleroticplaque and which directly or indirectly also induce smooth muscle cellproliferation. 13. Antithrombotics including but not limited to IIb/IIIainhibitors, Abciximab, heparin, clopidigrel, and warfarin.

[0083] The following Experiments are offered by way of illustration, notby way of limitation.

EXPERIMENTAL

[0084] Studies were performed to show visual and quantitative evidenceof depostion of agents in the adventitia and distribution of thedeposited agents from that site.

[0085] Distribution of fluorescent-labeled drug: Oregon Green® 488paclitaxel (OGP) was injected into balloon-injured or normal porcinecoronary arteries (15 arteries, 6 pigs) using a microneedle injectioncatheter having a needle with a diameter of 150 μm. Injections were madeto depths in the range from 0.8 mm to 1.2 mm One artery was treatedintraluminally with 5 mL OGP to determine background vascular uptake.Animals were sacrificed 0.5-23 hr post-procedure followingIACUC-approved protocol. After sacrifice, the LAD, RCA and LCx wereremoved, cut into 4-5 mm sections, which were frozen and cryosectioned.The slides were counter-stained with 0.1% Evan's Blue in PBS (5 min 37C) to quench autofluorescence, observed with a UV microscope, and scored0-4+. Representative sections were photographed.

[0086] Acutely harvested tissue (<2 hr post-procedure) showed 4+stainingof the adventitia when OGP was delivered with the microneedle catheterthrough the vessel wall. With increasing time after delivery, drugpenetrated into the media and extended longitudinally 13-24 mm (mean, 15mm) from the injection site. At 23 hr, staining was observed throughoutthe circumference of the artery, with longitudinal extension of 23-32 mm(mean, 27.5 mm). OGP delivered into the lumen without needle deploymentresulted in staining on the luminal surface only.

[0087] Distribution of silver nitrate: Two injections of 0.5 mL 5%Silver Nitrate were made into each iliac artery of a rabbit. The animalwas sacrificed according to approved protocol following the lastinjection. The arteries were removed and placed in 10% formalin withoutperfusion. 2 mm segments were embedded in paraffin, sectioned, andhematoxylin-eosin stained.

[0088] Staining showed delivery outside the external elastic lamina ofthe vessels and diffusion around the circumference.

[0089] Distribution of a lipophilic compound (tacrolimus): Eight swineunderwent angiography. Twenty-two coronary arteries (2.25-2.75 mm)received 125 micrograms tacrolimus in two 500 micrograms injectionsapproximately 1 cm apart. The two remaining arteries served as untreatedcontrols. An untreated heart was used as a negative control. At 48 hoursarteries were dissected from the musculature and perivascular fat, cutinto 5 mm sections and analyzed by Liquid Chromatography/MassSpectrometry against tacrolimus calibration standards containinghomogenized untreated porcine heart tissue.

[0090] In 8/8 subjects, periadventitial delivery of tacrolimus resultedin distribution to the entire coronary tree with higher concentrationsat injection sites. Drug was detected in 285/293 segments, includingside branches and uninjected arteries. The mean levels of tacrolimuswere 5.5 ng/100 mg tissue (SD=2.5, N=15) in the confirmed injectedarteries, 2.7 ng/100 mg tissue (SD=1.1, N=2) in uninjected arteries oftreated hearts, and 0.08 ng/100 mg tissue (SD=0.14, N=3) in uninjectedarteries of the untreated heart. Mean concentration within 1 cm of knowninjection sites was 6.4 ng/100 mg tissue (SD=3.7, N=13) versus 2.6ng/100 mg tissue (SD=1.5, N=13) in the remaining segments (p<0.001).Data are provided in FIGS. 9 and 10.

[0091] The microsyringe delivered agent to the adventitia, demonstratedby circumferential and longitudinal arterial distribution offluorescent-labeled paclitaxel and silver nitrate. The paclitaxelstudies showed that the distribution increased over time. Quantitativemeasurement of tacrolimus showed distribution of drug the full length ofthe artery, which was detectable 48 hours after injection.

[0092] A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention asclaimed hereinafter.

What is claimed is:
 1. A method for the volumetric distribution of apharmaceutical agent in the tissue of a living vertebrate host, saidmethod comprising: positioning a needle through the wall of a targetblood vessel so that an aperture of the needle is positioned beyond anexternal elastic lamina (EEL) of the wall by a distance not exceeding 5mm; and delivering an amount of the pharmaceutical agent from theaperture so that the agent distributes both longitudinally and radiallyfrom the injection site.
 2. A method as set in claim 1, wherein theagent distributes longitudinally along the blood vessel over a distanceof at least 1 cm and radially by a distance of at least 1 cm or within atime period no greater than 60 minutes.
 3. A method as in claim 2,wherein the concentrations of agent at all locations spaced at least 2cm from the delivery site are at least 10° of the concentration at thedelivery site.
 4. A method as in claim 1, wherein the agent distributesvia the lymphatic system surrounding the target.
 5. A method as in claim1, wherein the aperture of the needle is positioned at a distance lessthan 5 mm beyond the EEL.
 6. A method as in claim 5, whereinpharmaceutical agent comprises a small molecule drug, a protein, or agene.
 7. A method as in claim 6, wherein the agent has a maximumdimension of 200 nm or below.
 8. A method as in claim 1, wherein theblood vessel is a coronary blood vessel.
 9. A method as in claim 6,wherein the coronary blood vessel is an artery.
 10. A method as in claim7, wherein the coronary artery is at risk of hyperplasia.
 11. A methodas in claim 7, wherein the coronary artery has regions of vulnerableplaque.
 12. A method as in claim 1, wherein the patient is sufferingfrom congestive heart failure or a cardiac arrhythmia.
 13. A method asin claim 1, wherein the blood vessel is a cerebral blood vessel and thetissue is in the brain of the host.
 14. A method as in claim 1, whereinthe blood vessel is a hepatic blood vessel and the tissue is in theliver of the host.
 15. A method as in claim 1, wherein the agent isbeing delivered to treat a neoplastic disease in the tissue.
 16. Amethod as in claim 1, further comprising: confirming that the apertureis positioned beyond the EEL before delivering the amount ofpharmaceutical agent.
 17. An improved method for injecting apharmaceutical agent into the tissue of a living host using a needlepositioned from a lumen of a blood vessel, wherein the improvementcomprises positioning the needle outwardly from the blood vessel lumenand confirming that a delivery aperture of the needle has penetratedinto tissue beyond an external elastic lamina (EEL) of the blood vesselbefore injecting the pharmaceutical agent.
 18. An improved method as inclaim 17, wherein confirming comprises injecting contrast media throughthe needle aperture and observing distribution of the media.
 19. Animproved method as in claim 17, wherein confirming comprises monitoringinjection pressure.
 20. An improved method as in claim 17, whereinconfirming comprises monitoring temperature near the delivery aperture.21. An improved method as in claim 17, wherein confirming comprisesmonitoring pH near he delivery aperture.
 22. An improved method as inclaim 17, wherein confirming comprises monitoring electrical impedancenear the delivery aperture.
 23. An improved method as in claim 17,wherein confirming comprises monitoring insertion force whilepositioning the needle through the EEL.
 24. A catheter comprising: acatheter body; a needle having an aperture and being deployable from thecatheter body; and means coupled to the needle for detecting when theaperture of the needle has advanced beyond the external elastic laminaof the blood vessel.
 25. A catheter as in claim 24, wherein thedetecting means comprises a temperature sensor attached to the needlenear the aperture.
 26. A catheter as in claim 24, wherein the detectingmeans comprises an electrical impedance sensor attached to the needlenear the aperture.
 27. A catheter as in claim 24, wherein the detectingmeans comprises a pH sensor attached to the needle near the aperture.28. A catheter as in claim 24, wherein the detecting means comprises aninsertion force sensor coupled to the needle.
 29. A kit for delivering apharmaceutical agent to a patient suffering from or at risk of vasculardisease, said kit comprising: a catheter having a needle which can beadvanced from a blood vessel lumen through a wall of the blood vessel toposition an aperture of the needle beyond an external elastic lamina(EEL) of the wall by a distance not exceeding 5 mm; and instructions foruse setting forth a method comprising: positioning the needle throughthe wall of the target blood vessel so that the aperture of the needleis positioned beyond the external elastic lamina (EEL) of the wall by adistance not exceeding 5 mm; and delivering an amount of thepharmaceutical agent from the aperture so that the agent distributesboth longitudinally and radially from the injection site.